indroduction to Antibiotic resistance . .

indroduction to Antibiotic resistance .

1. Part 1:Antibiotics resistance MDR was defined as acquired non susceptibility to at least one agent in three or more antimicrobial categories , XDR was defined as non susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories ) PDR was defined as non-susceptibility to all agents in all antimicrobial Common multidrug-resistant organisms are usually bacteria: Vancomycin -Resistant Enterococci  (VRE) Methicillin -Resistant  Staphylococcus   aureus  ( MRSA ) Extended-spectrum β- lactamase  (ESBLs) producing Gram-negative bacteria Klebsiella   pneumoniae   carbapenemase  (KPC) producing Gram-negatives Multidrug-Resistant gram negative rods (MDR GNR) such as  Enterobacter  species ,  E.coli ,  Klebsiella pneumoniae ,  Acinetobacter baumannii ,  Pseudomonas aeruginosa A group of gram-positive and gram-negative bacteria of particular recent importance have been dubbed as the ESKAPE group ( Enterococcus faecium ,  Staphylococcus aureus ,  Klebsiella pneumoniae ,  Acinetobacter baumannii ,  Pseudomonas aeruginosa  and Enterobacter species).  Recognizing different degrees of MDR, the terms  extensively drug resistant  ( XDR ) and  pandrug -resistant ( PDR ) have been introduced. The definitions were published in 2011 in the journal  Clinical Microbiology and Infection  and are openly accessible

2. Emergence of resistance to multiple antimicrobial agents in pathogenic bacteria has become a significant public health threat as there are increasingly fewer, or even no effective antimicrobial agents available for infections caused by these bacteria. Gram-positive and gram-negative bacteria are both affected by the emergence and rise of antimicrobial resistance. In the strictest sense, multidrug-resistant organisms (MDROs) are labeled as such because of their resistance to more than one antimicrobial agent. Infections with MDROs can lead to inadequate or delayed antimicrobial therapy, and are associated with poorer patient outcomes . Of the MDROs, highly-resistant Gram-negative bacteria e.g. multidrug-resistant carbapenemase -producing Klebsiella pneumoniae and Acinetobacter spp. these organisms can be resistant to all currently available antimicrobial agents or remain susceptible only to older, potentially more toxic agents like the polymyxins , leaving limited and suboptimal options for treatment . No consensus has yet been reached on how to define terms such as “multidrug-resistant” (MDR), “extreme-drug resistant”, “extensive, extensively or extremely-drug resistant pandrug resistant” (PDR), which characterize resistance in MDROs. Moreover, accurate information cannot be conveyed to the public and to policy makers about the rising threat of MDROs to public health . Adopting standard definitions for bacteria that are resistant to a significant number of therapeutically active drugs would be an important step to improve surveillance of these organisms and better assess their global, regional and local epidemiological importance and public health impact.

3. Approaches to Creating Definitions of MDR, XDR, PDR the European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC), a first meeting of experts was held in Stockholm in January 2008 . The scope of the initial meeting was to create definitions for highly-resistant, multidrug-resistant bacteria associated with healthcare-associated infections. The expert group decided to concentrate on applying the definitions to S. aureus , Enterococcus spp., Enterobacteriaceae (other than Salmonella and Shigella ), P. aeruginosa , and Acinetobacter spp., because of the epidemiological significance, the emerging antimicrobial resistance and the importance of these bacteria within the healthcare system. bacterial isolate was considerd resistant, intermediate or non-susceptible when using interpretive criteria provided by European Committee on Antimicrobial Susceptibility Testing (EUCAST), the Clinical a nd Laboratory Standards Institute (CLSI) and/or the FDA . Only acquired antimicrobial resistance was used in creating definitions for MDR, XDR and PDR . Bacteria that are classified as XDR are epidemiologically significant due to their high degree of antimicrobial resistance, but also because they resistant to all, or almost all approved antimicrobial agents. In the medical literature XDR has been used for several different terms such as “extreme-drug resistance”, “extensive-drug resistance”, “extremely-drug resistant” and “extensively-drug resistant” Initially, the term XDR was created to describe extensively-drug resistant Mycobacterium tuberculosis (XDR MTB) and was defined as “resistance to the first-line agents isoniazid and rifampicin , to a fluoroquinolone and to at least one of the three second-line parenteral drugs (i.e. amikacin , kanamycin or capreomycin )

4. PDR From the Greek prefix pan-, meaning “all”, pandrug -resistant (PDR) means “resistant to all approved antimicrobial agents”. Even though this term is etymologically precise and mandates testing all approved and useful agents for a particular species and determining that a bacterial isolate of this species is resistant to all the agents, definitions in the literature for PDR still vary. Examples of current definitions are: “resistant to almost all commercially available antimicrobials”, “resistant to all antimicrobials routinely tested” and “resistant to all antibiotic classes available for empirical treatment” , making the definition of PDR subject to inconsistent use and liable to potential misinterpretation of data. Considerations in creating the definitions Initially, the expert group agreed that three issues needed to be addressed to develop the definitions: 1) how to create antimicrobial “categories” that would be epidemiologically useful , 2) how to select the antimicrobial categories and antimicrobial agents to be tested for each relevant bacterium, 3) how to define resistance within an antimicrobial category

5. How to detremain the breakpoint : The Food and Drug Administration (FDA) has not taken significant steps to ensure that antibiotic labels contain up-to-date breakpoints. Breakpoints are the concentrations at which bacteria are susceptible to successful treatment with an antibiotic. At a time when antibiotic resistance is increasing, long-time established breakpoints may under estimate antibiotic dosage levels, leading to under treatment of bacterial infections In the USA, the Clinical Laboratory Standards Institute (CLSI), formerly NCCLS , publishes such guidance

6. (a) Clinically resistant A micro-organism is defined as clinically resistant by a level of antimicrobial susceptibility which results in a higher than expected likelihood of therapeutic failure. A micro-organism is categorized as clinically resistant (R) by applying the appropriate breakpoint in a defined phenotypic test system. This breakpoint may be altered with changes in some circumstances. (b) Clinically susceptible A micro-organism is defined as clinically susceptible by a level of antimicrobial susceptibility which results in an improved, or the desired, therapeutic outcome. A micro-organism is categorised as clinically susceptible (s) by applying the appropriate breakpoint in a defined phenotypic test system. . (c) Clinically intermediate A micro-organism is defined as clinically intermediate by a level of antimicrobial susceptibility which results in an indeterminate therapeutic outcome. (d) Wild types and microbiological resistance Microbiological resistance is defined as a reduction in susceptibility from the wild type distribution of susceptibility for a species in a defined phenotypic test system. A micro-organism is categorised as belonging to the wild type (WT) for a species by applying the appropriate wild type cut-off value in a defined phenotypic test system . In order to categorize strains as susceptible, intermediate or resistant, breakpoint antibiotic concentrations are used .